Friday, May 29, 2009

The Sugar Fix: Chapter One: The Fructose Factor

Johnson starts The Sugar Fix with the assertion that a century ago heart disease, diabetes and obesity were rare conditions.

In 1890 a survey of 5,000 US citizens revealed that only 3.4% of Americans were obese and they were typically isolated to the upper class. This compares to a contemporary rate of 32%. Two thirds of Americans are either overweight or obese. This includes one third of school children. This obesity rate has doubled since 1976 (CDC Source). The rapid increase in girth cannot be explained by genetics. Johnson feels that the rapid change in the frequency of obesity exonerates genetics as the cause, he states that the human genome has been relatively stable going back a few thousand years.

This leaves an environmental change. He then considers and discards changes in physical activity as the etiology. This is supported by the most recent analysis revealed at the 2009 European Congress on Obesity.

Johnson goes on to implicate fructuse. He states that fructose intake has increased 30% since the 1970's. Fructose is the main source of sugar in fruit. It is half of the molecule sucrose, table sugar. In 1970 the average American consumed half a pound of High Fructose Corn Syrup. By 2000 that had increased to 42 pounds a year. Though HFCS consumption has risen by two orders of magnitude, fructose exposure has only gone up by 30%. This likely means that HFCS has largely replaced the prior source of fructose in the diet, table sugar. The authors don't address that inconsistancy in this chapter.

Fructose causes obesity through multiple mechanisms:
  • fructose causes more and faster weight gain than seen with other sugars
  • fructose does not satisfy your appetite resulting in more calorie intake
  • increased fructose dulls the brains responce to the normal satiety signals so that following chronic fructose exposure subjects eat more as they don't sence "fullness"
  • fructose upregulates enzymes which promote obesity
Johnson believes that other conditions have increased in prevalence in lockstep with the increased exposure to fructose including:
  • hypertension: 73 million Americans
  • diabetes: 20 million Americans (CDC Source)
  • kidney disease: 20 million Americans
  • liver disease: emergence of NASH, now effect 2-5% of Americans (NIDDK Source)
  • metabolic syndrome 55 million Americans
The mechanism linking fructose and these problems comes from multiple metabolic consequences of fructose:
  • fructose is the only sugar which increases the production of uric acid which leads to hypertension
  • fructose increases the production of triglyceridesand lowers HDL
  • fructose causes insulin resistance
  • fructose causes kidney disease
This last section is not supported by any references or data but Johnson promises to reveal the details later in the book.

Thursday, May 28, 2009

Great spoof ad on the impending Palm Pre

The heavy guy in blue is Roger McNamee, co-founder of Elevation Partners, a private equity group with a huge position in Palm. The video is a riff on episode a few months ago where McNamee caused quite a stir by overstoking the hype on the Pre, from Fortune:
In early March, McNamee caused a stir by telling a wire-service reporter that he thought the Pre was so good that customers would give up their iPhones as soon as their AT&T contracts expired. Palm was forced to file a statement with the SEC calling his comments "premature" and "an exaggerated prediction of consumer behavior."
The slender guy is Jon Rubenstein, one of the creators of the iPod from Apple and the lead designer of the Palm Pre.

The Sugar Fix: The Introduction

In the introduction of The Sugar Fix, Johnson uses a broad brush to establish the scope and purpose of what he intends to prove in the subsequent 300 pages.
  • He gives a brief anecdote about the increasing prevalence of obesity. His uric acid hypothesis is going to explain this huge health problem.
  • He outlines how he was initially looking for the cause of hypertension when he realized the weight-loss potential of a low fructose diet.
  • He then speeds through a handful of clinical studies, both epidemiologic and interventional, which implicate uric acid as a powerful risk factor for cardiovascular disease, i.e. uric acid as the new cholesterol. He admits that the scientific establishment has not accepted his theory as facts and that uric acid today is where smoking was in the 50s and cholesterol was in the 60s.
He concludes the chapter by disclosing two potential sources of bias. He is the Dr. Cade Professor of Medicine at the University of Florida and that his salary and research is supported by sales of Gatorade by the PepsiCo corporation. This is an interesting disclosure because the cola companies are the principle villains in this morality tale. I wonder if part of the reason for the release of Pepsi Throwback (sucrose rather than high-fructose corn syrup (HFCS) as the principle sweetener) is the pushback against HFCS partially lead by Dr. Johnson.

He also explains that he has applied for multiple patents that could financially benefit him if the relationship of uric acid and cardiovascular disease bears fruit.

Wednesday, May 27, 2009

Journal Club: Aggrenox and AVG for TZDs in HD

Dixon et al. Effect of dipyridamole plus aspirin on hemodialysis graft patency. N Engl J Med (2009) vol. 360 (21) pp. 2191-201 (PDF)

Randomized placebo controlled double blind trial of patients on hemodialysis or to start hemodialysis in the next 6 months with a new AVG.

Primary outcome was loss of primary unassisted graft patency. thrombosis, 50% stenosis. Patients underwent regular site monitoring and referred for angiography if qB was less than 600 or less than 1000 and a greater than 25% reduction of qB.

Power analysis required 1054 patients.

results: 321 randomized to Aggrenox
328 assigned to placebo

No difference in bleeding or cardiovascular events.

Take home message: modest benefit from expensive drug in underpowered but well designed and executed study.

Brunelli et al. Thiazolidinedione use is associated with better survival in hemodialysis patients with non-insulin dependent diabetes. Kidney Int (2009) vol. 75 (9) pp. 961-8 (pdf)

Thiazolidinediones (TZDs)
  • bind peroxisome proliferator-activated receptor gamma
  • increase insulin sensitivity in peripheral tissues
  • increase HDL
  • decrease triglycerides
  • decrease visceral fat
  • improve endothelial function
This study is a retrospective analysis of hemodialysis patients in the ArMORR cohort.
ArMORR is a cohort of incident dialysis patients at FMC units. The total cohort includes 10,044 patients.

This analysis restricted to patients with diabetes surviving at least 30 days on dialysis.

Patients on pioglitazone (Actos) or rosiglitazone (Avandia) were placed in the TZD group. Primary outcome was time to death from any cause. Maximum follow-up was one year.

Results: 5,290 patientss were eligible for inclusion.
9.6% were treated with a TZD

Improved survival was seen among patients on TZDs, especially patients not also on insulin. Interestingly the survival benefit came from a reduction of non-CV end-points.

Cool site on eGFR and proteinuria

2009 Annual Evidence Update on Proteinuria and eGFR

This Annual Evidence Update has been created to update the evidence presented last year for the 2008 National Knowledge Week on Proteinuria and eGFR. You can read commentaries on the latest systematic reviews, randomised controlled trials and the 2008 NICE guideline on Chronic Kidney Disease, as well as see what evidence has been produced in the last 12 months for the different topics presented last year. Drs David Goldsmith and Edward Sharples have also picked out the Treatment Uncertainties from the evidence, which have been added to the UK DUETs database.

UpToDate evidence based medicine or not? Not.

A few months ago medical blogger Laika wrote an insightful blog entry summarizing a meme which had been bouncing around twitter regarding whether UpToDate was evidence based medicine or some other entity.

I found the whole excercise to be a bit too philosophical for me. Regardless of what you call it I think everyone would agree that UpToDate is useful. It is a great starting place but usually insufficient as a single source.

I was reminded about it today when I came across this paragraph:

In the card on "Clinical manifestations, diagnosis, and natural history of primary biliary cirrhosis." (Link for subsribers)

Regardless of the merits of UpToDate, nothing breaks the illussion of evidence based medicine like an author throwing out a random statistic like "approximately 15% of the 1,200 patients who I have seen..." without a reference. This is the epitome of expert oriented experiential medicine and has no place in EBM.

Tuesday, May 26, 2009

I am doing Grand-Rounds on the relationship of uric acid and hypertension

About three years ago I had the privledge to attend a day long seminar on gout put together by Jerry Yee from Henry Ford Hospital. The highlight of the day was a lecture by Richard Johnson from the University of Florida. I had learned about Johnson at my fellowship as the principle discoverer of the link between hepatitis C and membranoproliferative glomerulonephritis (review), in my mind, among the most significant discoveries in nephrology in the last twenty years. Before seeing him I had not made the connection between Richard Johnson and the author of the deservedly popular nephrology text Comprehensive Clinical Nephrology, but it is one and the same.

At that seminar Dr. Johnson gave the greatest lecture I have ever heard. The lecture was on uric acid and its etiologic role in hypertension, obesity and diabetes.

When I heard that he was writing a book on the subject I purchased it and have been reading it on and off for the last 8 months or so. Unfortunately, the book doesn't have nearly the punch as his 90 minute lecture. My sense is that he writes to the level of the typical purchaser of diet books and comes across more as a carnival barker than one of the most respected researchers in nephrology today.

As I get ready for my grand rounds I am going to blog about uric acid, fructose and the epidemics of diabetes, obesity and hypertension as presented by Dr. Johnson in his book: The Sugar Fix. Should be an interesting ride as the subject is blessed with lots of data, industry influence, huge health implications and a likely Nobel prize if Johnson has really discovered the cause of the bulk of essential hypertension.

Thursday, May 21, 2009

PBFluids has been a little quiet recently

In the past few weeks I have been working on two presentations. The first was to Genzyme's scientists and the second was grand rounds at Providence. I have been spending way too much time working on those two talks. Thankfully the bones of both talks were the same. I spoke on the problem of chronic kidney disease on the elderly, specifically whether CKD was over diagnosed (yes it is) in this population and can it be safely ignored (no it can't).

I'm not completely through the gauntlet yet. I still have to provide a chapter on lifestyle modification for the control of blood pressure.

But I can't describe the awesome feeling of relief from delivering the grand rounds this morning.

For those of you with iWork and Keynote here is the presentation:

The Two Faces of Geriatric CKD

Wednesday, May 13, 2009

RTA Lecture for Medicine Board Review

I gave my third board review class for the graduating residents at Providence. They requested RTAs. Here are the supporting materials:
  • Power point presentation (link)
  • Active ABG problem generator (link)

Good luck.

Cool new (to me) word: Anamnesis

Learned a new word: anamnesis.

Synonym for medical history.

Apparently, if you are considering the diagnosis of HCl intoxication no fancy flow chart needed just ask the patient if she's been swigging hydrochloric acid.

Sterile Pyuria [updated]

Patient came in yesterday with a three month history of frequent UTIs. These UTIs were diagnosed when the patient presented to her doctor with back/flank pain and the U/A was positive for leukocyte esterase and white cells but was always nitrate negative and the cultures never revealed more than low colony counts of skin flora.

The patient's pain repeatedly responded to a few days of quinolone therapy.

Differential for sterile pyuria:
  • Renal TB: patient's husband had a history of active TB
  • Interstitial nephritis: patient was taking a significant amount of NSAIDs and ASA for the back pain
  • Nephrolithiasis: patient had calcifications in the kidney on the U/S
  • Urogenital cancer
  • Vaginal contamination
  • Glomerulonephritis
  • Chlamydia, mycoplasma, ureaplasma (thanks Jim)

Monday, May 11, 2009

Weight loss and blood pressure

Hmm, that's an interesting question. When I counsel patients on controlling blood pressure I mention weight loss but don't perseverate on it because of the general futility of of achieving lasting weight loss. Most diets deliver only modest weight loss and that weight loss is depressingly short lived:
The figure above is the primary results from a trial of various strategies to preserve weight loss. 1,685 patients were enrolled, only 1,032 lost the require 10 lbs to begin Phase 2. In Phase 2 patients were randomized to 1) minimal intervention 2) web-based interaction 3) monthly contact with an interventionist. Patients with monthly contact regained 3 lbs less than the patients with self-directed maintenance. Svetkey et al. Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial. JAMA (2008) vol. 299 (10) pp. 1139-48 (PDF)

Second study looking at Weight Watchers compared to a self-help program for weight loss. Same pattern, modest weight loss followed by rebound to regain much of the lost weight. Heshka et al. Weight loss with self-help compared with a structured commercial program: a randomized trial. JAMA (2003) vol. 289 (14) pp. 1792-8 (PDF)

I focus my limited office time on changing patients' diet to reduce blood pressure. I recommend the DASH diet (PDF) to all of my patients without significant metabolic bone disease or hyperkalemia because I believe the data shows that it is the most effective life-style intervention to ameliorate hypertension. Unfortunately those two exclusions (bone disease and potassium) exclude many of my patients. I usually don't recommend the low sodium version of of DASH because I feel that the reduction in palatability is not supported by the rather modest additive effects (an additional 3 mmHg reduction in SBP). Most of my patients recognize that they eat too much and have been trying to reduce calories, and lose weight for years prior to seeing me. I feel that by discussing the DASH diet and not rehashing the same tired dietary advice that every doctor has been promoting, I provide them with a novel view of dietary changes that they are willing to try.

Still, I think The Kidney Group has an interesting question, what is more important weight loss or diet changes?

NephSAP recently reviewed hypertension. On page 98 they had this table which compared various lifestyle interventions and their effect on blood pressure:
Unfortunately they grouped diet and weight loss in one group so it does not allow me to separate out the effect of changing diet from changing weight. Regardless, the effect on blood pressure looks modest compared to the findings of the DASH diet or DASH sodium intervention. From the abstract of the DASH-Sodium trial (PDF):
As compared with the control diet with a high sodium level, the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension, and 11.5 mm Hg lower in participants with hypertension.
The Archive published this meta-analysis (PDF) in 2008 looking at weight loss by diet or drugs with respect to mortality and blood pressure control.

They found that weight loss did result in blood pressure reductions but the reduction was modest. Additionally not all methods were equal, with silbutamide (Meridia) resulting in an increase in blood pressure despite being effective at reducing weight. They were unable to find any studies which showed a reduction in weight reducing mortality.

The above systemic review mentioned that the TONE study was one that was particularly well done. The TONE trial (PDF) was published in JAMA in 1998 and compared sodium restriction to weight loss to usual care in a two by two factorial design. The enrolled 585 obese patients to be randomized to either weight loss, no weight loss, salt restriction or not. Another 390 were randomized to either salt restriction or usual diet.
The investigators achieved nice separation of the groups with regard to weight loss. The study began with every patient weaning off their antihypertensive medication and the primary end-point was the fraction resuming their pharmacologic blood pressure medications and the time to resumption. Weight loss was more effective than no intervention and about equally efficacious as sodium restriction:

Note the lower starting blood pressure for sodium intake, this accounts for some of the difference in the effect on blood pressure.

Though TONE showed no difference between weight loss and sodium restriction, I feel that diet is probably more important because sodium restrictionis not the most effective dietary change to reduce blood pressure, the DASH diet is. I feel that if the TONE trial was rerun with the DASH diet replacing sodium restriction we might see that diet is more important than weight loss.

One thing I am doing in my clinic more and more is recommending bariatric surgery. Medical and behavioral changes have a poor track record at providing lasting and significant weight loss. Bariatric surgery shows lasting weight loss 10 years out and it allows patients to recover from hypertension and diabetes. Sjöström et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med (2004) vol. 351 (26) pp. 2683-93. (PDF)

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